Treatment of Rabbit Rotator Cuff Fatty Infiltration and Atrophy with Electric Stimulation and a PDGFRa inhibitor

电刺激和 PDGFRa 抑制剂治疗兔肩袖脂肪浸润和萎缩

• 批准号: 10641248
• 负责人: Mohit Gilotra
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-10-01 至 2028-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641248
• 关键词: Acute; Adipocytes; Affect; Alpha Cell; Animal Model; Animals; Atrophic; Award; Biology; Biopsy; Cells; Chronic; Clinical; Clinical Trials; Data; Diagnosis; Disuse Atrophy; Electric Stimulation; Euthanasia; Exhibits; FDA approved; Fatigue; Fatty acid glycerol esters; Fibrosis; Frequencies; Future; Gait; Goals; Healthcare Systems; Histology; Human; Hyperplasia; Image; Imaging Techniques; Immobilization; Incidence; Infiltration; Injury; Intervention; Lead; Maryland; Measures; Mechanics; Mesenchymal; Methods; Modeling; Mus; Muscle; Muscle function; Muscular Atrophy; Natural regeneration; Operative Surgical Procedures; Orthopedics; Oryctolagus cuniculus; Outcome; Outcome Measure; Outcome Study; PDGFA gene; Patients; Pattern; Pharmaceutical Preparations; Physiologic pulse; Physiological; Platelet-Derived Growth Factor Receptor; Platelet-Derived Growth Factor alpha Receptor; Prevention; Probability; Prognostic Factor; Property; Receptor Inhibition; Recovery; Rehabilitation therapy; Reproducibility; Research; Research Design; Research Methodology; Research Personnel; Research Support; Rotator Cuff; Scientist; Shoulder; Surgeon; Tendon structure; Testing; Tetany; Time; Tissues; United States Department of Veterans Affairs; Veterans; Work; X-Ray Computed Tomography; adipocyte biology; antagonist; career; disability; experience; functional improvement; functional outcomes; gait examination; healing; improved; improved outcome; in vivo; in vivo Model; inhibitor; microCT; military veteran; mouse model; muscle physiology; muscle regeneration; non-invasive imaging; novel; pain reduction; pharmacologic; pre-clinical; preservation; prevent; programs; rehabilitation research; repair model; repaired; research and development; rotator cuff injury; rotator cuff tear; supraspinatus muscle; translational research program; viscoelasticity

Background: The PI proposes to test the hypothesis that inhibition of platelet-derived growth factor receptor alpha (PDGFRa) and direct, submaximal electric stimulation (ES) synergistically prevents fatty infiltration (FI) and muscle atrophy, improving function after rotator cuff tear. A large irreparable rotator cuff tear with muscle FI is one of the most common diagnoses seen in his VA practice. According to the Veterans Administration Surgical Quality Improvement Program, over 10,000 Veterans with rotator cuff injuries underwent rotator cuff repairs over a six-year span. Surgical repair of a torn rotator cuff is generally successful, though with a re-tear rate of 25 percent. We propose a novel method of FI prevention and will study how this affects muscle function. Fatty infiltration and atrophy leads to poor outcomes from tendon re-tear and decreased muscle function. Objectives: The overall purpose of this proposal is to determine whether the treatment of FI and atrophy improves outcomes in a rabbit animal model such as: animal gait, muscle function, and rotator cuff healing.  Aim 1: Determine if PDGFR inhibition and direct muscle ES at the time of rotator cuff tear can improve muscle function by preventing FI and atrophy in an established rabbit rotator cuff tear model.  Aim 2: Determine if PDGFR inhibition and direct muscle ES can arrest/impede FI and improve function using a delayed repair model in which FI and atrophy have been established. Research Design and Methodology: This study will utilize an established and reproducible rabbit in vivo model of chronic rotator cuff tear and muscle fatty infiltration in Aims 1 and 2. Study outcome measures for both aims include: in vivo contractile muscle function testing, rabbit gait analysis, quantitative-based micro-CT imaging of muscle fatty infiltration, tissue analysis for fibro-adipogenic cells and fat/fibrosis specific histology. Specific Aim 2 will utilize these same outcomes, as well as tendon functional testing to determine viscoelastic properties. Clinical Relationships: Rotator cuff tear with irreversible FI is common in the Veteran population and precludes a successful repair and outcome. The ultimate goal is finding novel interventions that can improve function for Veterans undergoing rotator cuff repair. Impact/Significance: The proposed Merit Award will lay the groundwork for future clinical trials within the next ten years by testing two Federal Drug Agency approved treatments for their synergistic effects on the treatment of atrophic rotator cuff tears. This translational pre-clinical approach has the potential to: reduce pain and improve Veteran's ability to function independently and return to physical work. Furthermore, it will provide valuable research support for the applicant as he pursues a career as an orthopaedic surgeon-scientist at the VA Maryland Health Care System. [The PI has a team of three co-investigators experienced in rotator cuff imaging, rotator cuff muscle physiology and adipocyte formation.]

背景：PI提案，以检验抑制血小板衍生生长因子的假设 受体α（PDGFRA）和直接的，次最大的电刺激（ES）协同防止脂肪 浸润（FI）和肌肉萎缩，肩袖撕裂后的功能改善。一个不可弥补的旋转器 用肌肉fi袖口撕裂是他VA实践中最常见的诊断之一。根据 退伍军人管理手术质量改进计划，超过10,000多名带有肩袖的退伍军人 伤害在六年的时间内进行了肩袖维修。撕裂肩袖的手术修复是 通常成功的速度为25％。我们提出了一种新颖的FI方法 预防并将研究这如何影响肌肉功能。 脂肪浸润和萎缩会导致肌腱重新弯曲和改善的肌肉结果不佳 功能。目标：该提案的总体目的是确定是否处理 FI和萎缩改善了兔动物模型的结局，例如：动物步态，肌肉功能和 肩袖愈合。 目标1：确定肩袖撕裂时PDGFR抑制和直接肌肉是否可以 通过预防已建立的兔肩袖的FI和萎缩来改善肌肉功能 撕裂模型。 目标2：确定PDGFR抑制和直接肌肉ES是否可以逮捕/妨碍FI和 使用延迟的维修模型提高功能，其中FI和萎缩已成为 已确立的。 研究设计和方法论：本研究将利用既定的兔子 在目标1和2中的慢性肩袖撕裂和肌肉脂肪浸润的体内模型。研究结果 这两个目标的措施包括：体内转换器肌肉功能测试，兔步态分析， 基于定量的肌肉脂肪浸润的微CT成像，纤维辅助组织的组织分析 细胞和脂肪/纤维化特异性组织学。具体目标2将利用这些相同的结果以及 肌腱功能测试以确定粘弹性特性。 临床关系：在退伍军人人群中常见的肩袖撕裂和不可逆的FI很常见 排除了成功的维修和结果。最终目标是寻找可以 改善接受肩袖修复的退伍军人的功能。 影响/意义：拟议的优异奖将为将来的临床试验奠定基础 接下来的十年，通过测试两家联邦药物局的协同作用批准治疗 治疗萎缩肩袖撕裂。这种翻译的临床前方法具有潜力 TO：减轻疼痛并提高退伍军人独立运作并恢复体力劳动的能力。 此外，它将为申请人提供宝贵的研究支持，因为他从事职业 VA马里兰州卫生保健系统的骨科外科医生科学家。 [PI有三个团队 肩袖成像，肩袖肌肉生理学和脂肪细胞的共同研究器 编队。]